1. Project Summary Prevalence of Alzheimer?s disease (AD) and related dementias, currently affecting an estimated 5.5 million Americans, is expected to triple by 2050. With no available treatments, emphasis has shifted toward preventive strategies through midlife risk factor reduction. Several lines of evidence suggest that cardiovascular disease (CVD) and various CVD risk factors are strongly associated with future incidence of dementia. Vascular risk factors are easily identifiable and often modifiable. Therefore, discovery of vascular biomarkers and early risk factors that precede both CVD and cognitive decline would significantly enhance progress toward novel preventive strategies for dementia. However, modifiable and noninvasive vascular biomarkers that precede clinical CVD, subclinical AD pathology, and cognitive decline are lacking. Thus, identification of early, modifiable, and noninvasive vascular biomarkers is considered a research priority by the NIH, American Heart/Stroke Associations, and the Alzheimer?s Association. One such potential biomarker is heart rate variability (HRV), the beat-to-beat temporal variation in normal sinus rhythm. HRV is used clinically as a standard, noninvasive and modifiable index of cardiac autonomic function, with higher HRV indicating stronger autonomic tone over the heart. Abnormally reduced HRV during midlife indicates cardiac autonomic dysfunction and is strongly associated with future incidence of CVD as well as with various modifiable and non- modifiable cognitive risk factors. Yet, its direct association with cognitive performance is unclear, and it is still unknown whether an association exists between HRV and subclinical AD pathologies including brain ?-amyloid (A?) deposition, reduced brain volume, and vascular white matter hyperintensity (WMH) lesions. Therefore, we propose to study cross-sectional and longitudinal associations among HRV, cognitive performance, and AD pathology in an aging multi-ethnic cohort of male and female US adult participants in the ongoing, NIH- sponsored Multi-Ethnic Study of Atherosclerosis (MESA). In Aim 1 we will investigate the relationship between antecedent and contemporaneous short-term (10-s) HRV and performance on cognitive tests indexing global cognitive performance, processing speed, and working memory administered to all participants. This aim will clarify the inconsistent evidence for associations between short-term HRV and cognitive performance across various cognitive domains. In Aim 2 we will determine if an association exists between contemporaneous long- term (24-h) ambulatory HRV and performance on an extensive cognitive battery, brain A? deposition, total brain volume, and WMH burden in a subset of MESA participants with detailed HRV, cognitive, and brain imaging data. If successful, the proposed study will provide evidence of 10-s and 24-h ambulatory HRV as practical, noninvasive and modifiable early biomarkers of cognitive performance and AD-related neuropathology in the general population of middle-aged and elderly US adults.